2013 19: vii-xiRNAR.R. Gutell2012)−Woese (1928You tell Carl that some of my best friends are Eukaryotes: Carl R.References...
You tell Carl that some of my best friends are Eukaryotes:Carl R. Woese (1928–2012)I cherished the opportunity to have Dr....
identified several tertiary structure base pairs, some com-posed of canonical G:C, A:U, and G:U base pairs, others com-pos...
“universal phylogenetic framework” was needed. Carl alsorealized that the evolutionary relationships between bacteriawere ...
Some millions of years later, another cell separated itselffrom the community and became the ancestor of thearchea. Some t...
Orgel LE. 1968. Evolution of the genetic apparatus. J Mol Biol 38:381–393.Orgel LE, Crick FH. 1993. Anticipating an RNA wo...
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Gutell R.R. (2013).
You tell Carl that some of my best friends are Eukaryotes: Carl R. Woese (1928-2012).
RNA, 19(4):vii-xi.

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Gutell 124.rna 2013-woese-19-vii-xi

  1. 1. 2013 19: vii-xiRNAR.R. Gutell2012)−Woese (1928You tell Carl that some of my best friends are Eukaryotes: Carl R.Referenceshttp://rnajournal.cshlp.org/content/19/4/vii.full.html#ref-list-1This article cites 34 articles, 18 of which can be accessed free at:serviceEmail alertingclick heretop right corner of the article orReceive free email alerts when new articles cite this article - sign up in the box at thehttp://rnajournal.cshlp.org/subscriptionsgo to:RNATo subscribe toCopyright © 2013 RNA SocietyCold Spring Harbor Laboratory Presson March 19, 2013 - Published byrnajournal.cshlp.orgDownloaded from
  2. 2. You tell Carl that some of my best friends are Eukaryotes:Carl R. Woese (1928–2012)I cherished the opportunity to have Dr. Carl Woese as one ofmy mentors and collaborators. While I and many others aredeeply saddened by his death on December 30, 2012, we areso grateful for his many contributions to science and for themany ways he enlightened our lives. His wisdom and encour-agement are most appreciated.Shortly after I started graduate school in the late 1970s tostudy the structure and function of the ribosome at theUniversity of California at Santa Cruz, my advisor, Dr. HarryNoller, posted this November 3, 1977, New York Times articleon the front door to his lab: “Scientists discover a form of lifethat predates higher organisms” (Woese and Fox 1977a).LittledidIknowatthetimethatthisdescriptionaboutthethirdform of life, discovered by Drs. Carl Woese and George Fox,would establish the foundation for my entire professional ca-reer, influence the scientific careers for many (many) scien-tists, while making a profound contribution to severalprimary disciplines in biology.One of my first projects in Harry’s lab was to help solvethe secondary structure for the Escherichia coli 16S and 23SrRNA. We quickly determined that the number of possiblerRNA secondary structure models was more than the num-ber of elemental particles in the universe. This problem wasexacerbated by the lack of adequate energy values for all ofthe simple RNA structural elements and motifs that collec-tively form the higher-order structure for RNA molecules.Thus we could not discern, based on first principles, whichof the many possible structure models were correct. I consid-ered my first project in Harry’s lab to be a failure. FortunatelyHarry and Carl were good friends and Carl encouraged Harryto use comparative methods to identify the 16S rRNA sec-ondary structure that is common for a set of 16S rRNA se-quences from different organisms. I have fond memories ofCarl visiting Santa Cruz to collaborate on this project. Theminimal secondary structure for the 16S rRNA (and later23S rRNA) was determined in the early 1980s (Woese et al.1980; Noller et al. 1981). Although people questioned atthe onset this nonbiophysical method of determining anRNA’s secondary structure, scientists started to embrace thismethod when the resulting secondary structure models wereconsistent with their experimental results while providing abetter framework to interpret their experiments and speculateabout the structure and function of their biological system.These 16S and 23S rRNA secondary structure models wererefined as the number and diversity of sequences increaseddramatically in parallel with the development of more com-putationally rigorous covariation methods. The authenticityof these comparative structure models was evaluated whenthe high-resolution crystalstructuresfor the 30S and 50S ribo-somal subunits were determined in 2000. I doubt that GregorMendel could have done better. Approximately 98% of thebase pairs predicted with the covariation methods were pre-sent in these high-resolution crystal structures (Gutell et al.2002).Once it became apparent to a growing number of molec-ular biologists that comparative methods had the potentialto accurately determine an RNA’s secondary structure, somepeople, including me, believed that comparative methods“had served its purpose.” It was now time for other methodsto elucidate more details about RNA structure. Not accordingto Carl and Harry. I received a paper from Carl, written byMichael Levitt (1969), revealing that comparative methodswere used to accurately predict a few of the tertiary structureinteractions in tRNA. Thus I turned down a few postdocoffers in experimental labs to continue my comparative anal-ysis of the rRNAs in Carl’s lab at the University of Illinois. We(Photo Courtesy Don Hamerman)RNA (2013) Published by Cold Spring Harbor Laboratory Press. Copyright © 2013 RNA Society. viiCold Spring Harbor Laboratory Presson March 19, 2013 - Published byrnajournal.cshlp.orgDownloaded from
  3. 3. identified several tertiary structure base pairs, some com-posed of canonical G:C, A:U, and G:U base pairs, others com-posed of noncanonical base pair and exchanges, includingU:U <-> C:C, G:A <-> A:G, A:A <-> G:G, G:U < > A:C.Other irregular structural elements were identified, includingsingle or lone base pairs, lone base pairs capped with a 3-nu-cleotide hairpin loop, base pairs forming pseudoknots, paral-lel (vs. anti-parallel) arrangement of consecutive base pairs,base triples, and other novel structural elements (Gutellet al. 1986; Woese and Gutell 1989; Gutell and Woese 1990).All of these noncanonical structural elements were presentin the high-resolution crystal structure (Gutell et al. 2002).These latter studies revealed that comparative analysis cannot only identify the correct canonical secondary structure,but can begin to identify and characterize new types of struc-tural elements.After these discoveries of irregular structural elementsbased on covariation analysis, some of us questioned againwhether comparative analysis can reveal more about RNAstructure. And again Carl had more to contribute. Carl hadan amazing ability to see patterns in the secondary structurediagrams. While in hindsight it is obvious, Carl first noticedthat the majority of the hairpin loops in 16S rRNA had onlyfour nucleotides, and only 10 or so of the 256 sequences oflength four were present at nearly all of the bacterial tetra-loops (Woese et al. 1990). We observed other biased distribu-tions of nucleotides on several structural elements, includingthe large abundance of unpaired adenosines (Gutell et al.1985, 1994). Thus, comparative analysis could be used toidentify and characterize RNA structural motifs, the basicbuilding blocks of RNA structure.Possibly one of the most audacious statements Carl wrote(from my perspective) was published in 1983. At that time,Carl and Harry were publishing our first “minimal” compar-ative secondary structure models for the 16S and 23S rRNAs.While some people were skeptical of these models, both of mymentors had utmost confidence in them. Carl knew that com-parative analysis could reveal more than “just” the secondarystructure base pairs:“The comparative approach indicates far more than themere existence of a secondary structural element; it ulti-mately providesthe detailed rules for constructing the func-tional form of each helix. Such rules are a transformationof the detailed physical relationships of a helix and perhapseven reflection of its detailed energetics as well. (One mightenvision a future time when comparative sequencing pro-vides energetic measurements too subtle for physical chem-ical measurements to determine.)” (Woese et al. 1983.)My lab and others have used comparative methods to derivepseudo-energies (statistical potentials) that are a bit moreaccurate than experimentally determined energy values forstructural elements (Do et al. 2006; Andronescu et al. 2010;Gardner et al. 2011).Carl did not mince his words when he believed that thescientists were working under the pretenses of a faulty para-digm. Possibly a better example of Carl’s chutzpah follows inhis presentation entitled “Just so stories and Rube Goldbergmachines: Speculations on the origin of the protein syntheticmachinery” at the 1980 ribosome conference (Woese 1980).Carl wrote:“The organizers of this Symposium have asked me tospeak on the topic ‘Speculations on the Origin of theProtein Synthetic Machinery’, which I have appropriatelyretitled ‘Just-So Stories, and Rube Goldberg Machines’.The topic is a challenging but frustrating one. It is chal-lenging because in order to address it properly one is forcedinto the much-needed reexamination of our concept oftranslation and its relationship to Biology as a whole. Itis frustrating for two reasons: For one, unavoidably Iwill have to present a Just-So Story. What do we reallyknow about how translation works at the molecular level?We know nothing! How then, does one explain the evolu-tion of an unknown mechanism? By a Just-So Story! Mysecond reason is that this presentation will at best elicit aho-hum response; the field is atune to a paradigm thatsees little value in understanding how translation evolved.From the set of codon assignments on down all facets of thetranslation mechanism are taken as arising by ‘historicalaccident’, as being un-repeatable evolutionary events.This can and has given rise to the prejudice that the trans-lation apparatus is basically a Rube Goldberg Machine—some incongruous assemblage of parts, where knowingeven ninety percent of the mechanism would not permitone to predict the remaining ten percent. The RubeGoldberg view not only generates disinterest in the mech-anism’s evolution, but also leads to a feeling that there isno point in attempting to think, to theorize about a mech-anism that is unknowable a priori; one’s approach needsto be ‘strictly empirical’. If this presentation serves no otherpurpose, I should like it to raise the issue of the design ofthe translation apparatus; Is it really a Rube GoldbergMachine? Is there a simple mechanism at its core? Bywhat principles does it achieve its low noise level? Doesit possess an understandable evolutionary structure?”Although these accomplishments are most significant,Carl is mostly recognized for his studies on the evolution oforganisms, not RNA.The development of Carl’s scientific inquiries was influ-enced by the discovery of DNA’s double helix structurenear the time he completed his PhD at Yale (Woese 2004).Like others at that time, he was intrigued with the geneticcode. However, the simple assignments of codons to aminoacids did not satisfy his curiosity about translation. Carl start-ed questioning what was special about the relationship be-tween the genotype and phenotype, the mechanism oftranslation, and how these relationships and mechanismsevolved. And to resolve these issues, Carl realized that aviiiIn memoriamCold Spring Harbor Laboratory Presson March 19, 2013 - Published byrnajournal.cshlp.orgDownloaded from
  4. 4. “universal phylogenetic framework” was needed. Carl alsorealized that the evolutionary relationships between bacteriawere unknown, although their abundance was significantlygreater than that for animals and plants. The seeds for at leastpart of Carl’s scientific career were planted.Carl (and George Fox) also realized that any attempt tounderstand the evolution of one of the most fundamentalmechanisms of the cell—protein synthesis—brought themface to face with the origin of cellular life. Thus, not onlywere they trying to reconstruct the phylogenetic relationshipsfor all organisms, they were trying to decipher the molecularand cellular events that occurred shortly before and after theorigin of cellular life. They published one of my favorite pa-pers, “The Concept of Cellular Evolution” (Woese and Fox1977b), the year I started graduate school. The concept ofthe Progenote—the predecessor to the cellular life as we cur-rently know it—was introduced.Utilizing new nucleic-acid sequencing technology devel-oped by Fred Sanger, Carl started his majestic effort to deter-mine the evolutionary relationships for prokaryotes and relatethem with eukaryotes. Carl and George reasoned (Woese andFox 1977a; Woese 1987) that the analysis of “comparablestructures” that are (1) present in all life forms and (2) atthe core of the fundamental cellular mechanisms in the cellis necessary to reconstruct phylogenetic relationships thatspan the entire tree of life. That core, as they defined it, wasthe ribosome’s translation of the cell’s genotype to its pheno-type. They rationalized that the evolution of the ribosomalRNAs, to a first approximation, would be neutral to the envi-ronment and their evolution would be slower than othergenetic sequences. Although the ribosomal RNA satisfiedthese criteria, the majority of macromolecular sequencesevolves too quickly and thus can only be used to determinephylogenetic relationships for a small region of the phyloge-netic tree, not for the full spectrum of life forms. Since itwas also rationalized that RNA was present before DNA andproteins (Woese 1967; Crick 1968; Orgel 1968) and that ribo-somal RNA was directly associated with the translation of thecell’s genotype to its phenotype (Woese and Fox 1977b), ananalysis of rRNA might reveal the early stages in the originof life during the transition between the progenote andthe original forms of the Archaea, Bacteria, and Eukaryotes.These seminal concepts were the foundation for the determi-nation of rRNA sequences for organisms that span the entiretree of life, resulting in (1) the discovery of the Archaea as thethird form of life; (2) the first phylogenetic trees that containrepresentative organisms from the full spectrum of all liv-ing forms (Woese 1987, 2000); (3) the massive communityeffort to determine rRNA sequences from all forms of life re-sulting in the largest collection of sequence data for any onegene; (4) the use of rRNA sequences for medical diagnosticpurposes (e.g., Gen-Probe, http://www.gen-probe.com/science/#technologies-3); and (5) the analysisof microbiomeswith16SrRNAsequencingrevealinghowprevalent,pervasive,and important Bacteria and Archaea are for the survival andhealth of multicellular organisms and different environmentson earth. One editorial published in Nature ReviewsMicrobiology (Editorial 2011) described a compelling reasonwhy Carl Woese should win the Nobel Prize:“Carl Woese has completely changed the way we view therelationships between all organisms on Earth, revealed thepresence of a previously unrecognized domain and provid-ed us with a tool that has begun to elucidate the complexcomposition of the human microbiome, which constitutes90% of the genetic diversity of our bodies and has beencalled the second human genome. It is difficult to thinkof more-fundamental discoveries that are affecting theway we think about the environment and human healthalike. As the attentions of the scientific community turnonce again to the decisions of the Nobel committee, per-haps it is time to campaign for Carl Woese to receive therecognition that he deserves.”Carl also addressed a multitude of related topics, includingmitochondrial origins (Woese 1977; Yang et al. 1985); the ge-netic code (Woese 1965a,b, 1967, 1969; 1970a,c; 1973; Woeseet al. 1966); speculated that RNA came before DNA and pro-teins, which published a year before Francis Crick and LeslieOrgel published similar speculations (Woese 1967; Crick1968; Orgel 1968; Orgel and Crick 1993); more speculationsabout the mechanisms of translation (Woese 1970b; Woese2001); and the use of comparative analysis to predict the (cor-rect) secondary structure for 5S rRNA (Fox and Woese 1975).“A new biology for a new century” is one of my favoritearticles written by Carl (Woese 2004). Freeman Dyson de-scribes it with much eloquence (Dyson 2007):“Whatever Carl Woese writes, even in a speculative vein,needs to be taken seriously. In his ‘New Biology’ article, heis postulating a golden age of pre-Darwinian life, whenhorizontal gene transfer was universal and separate speciesdid not yet exist. Life was then a community of cells of var-ious kinds, sharing their genetic information so that cleverchemical tricks and catalytic processes invented by onecreature could be inherited by all of them. Evolution wasa communal affair, the whole community advancing inmetabolic and reproductive efficiency as the genes of themost efficient cells were shared. Evolution could be rapid,as new chemical devices could be evolved simultaneouslyby cells of different kinds working in parallel and then re-assembled in a single cell by horizontal gene transfer.“But then, one evil day, a cell resembling a primitivebacterium happened to find itself one jump ahead of itsneighbors in efficiency. That cell, separated itself fromthe community and refused to share. Its offspring becamethe first species of bacteria—and the first species of anykind—reserving their intellectual property for their ownprivate use. With their superior efficiency, the bacteriacontinued to prosper and to evolve separately, while therest of the community continued its communal life.www.rnajournal.org ixIn memoriamCold Spring Harbor Laboratory Presson March 19, 2013 - Published byrnajournal.cshlp.orgDownloaded from
  5. 5. Some millions of years later, another cell separated itselffrom the community and became the ancestor of thearchea. Some time after that, a third cell separated itselfand became the ancestor of the eukaryotes. And so itwent on, until nothing was left of the community andall life was divided into species. The Darwinian interludehad begun.”Now quoting directly from Carl’s “A new biology for a newcentury” (Woese 2004):“Let’s stop looking at the organism purely as a molecularmachine. The machine metaphor certainly provides in-sights, but these come at the price of overlooking muchof what biology is. Machines are not made of parts thatcontinually turn over, renew. The organism is. Machinesare stable and accurate because they are designed and builtto be so. The stability of an organism lies in resilience, thehomeostatic capacity to reestablish itself. While a machineis a mere collection of parts, some sort of ‘sense of the whole’inheresintheorganism,aqualitythatbecomesparticularlyapparent in phenomena such as regeneration in amphibi-ans and certain invertebrates and in the homeorhesis ex-hibited by developing embryos.“If they are not machines, then what are organisms? Ametaphorfarmoretomylikingisthis.Imagineachildplay-ing inawoodland stream, poking a stick into an eddy in theflowing current, thereby disrupting it. But the eddy quicklyreforms. The child disperses it again. Again it reforms, andthe fascinating game goes on. Thereyou have it! Organismsare resilient patterns in a turbulent flow—patterns in anenergy flow. A simple flow metaphor, of course, fails to cap-ture much of what the organism is. None of our representa-tions of organism capture it in its entirety. But the flowmetaphor does begin to show us the organism’s (and biol-ogy’s) essence. And it is becoming increasingly clear thatto understand living systems in any deep sense, we mustcome to see them not materialistically, as machines, butas (stable) complex, dynamic organization.“Twenty-first century biology will concern itself withthe great ‘nonreductionist’ 19thcentury biological prob-lems that molecular biology left untouched. All of theseproblems are different aspects of one of the great problemsin all of science, namely, the nature of (complex) organiza-tion. Evolution represents its dynamic, generative aspect;morphology and morphogenesis represent its emergent,material aspect. One can already see the problem of theevolution of cellular organization coming to the fore. Andbecause of both its pressing practical and its fundamentalnature, the problem of the basic structure of the biosphereis doing so as well.“My own career is one of the links between biology’sreductionist molecular past and its holistic future.”Although Carl had already discovered the third domain oflife, proposed that RNA came before DNA and proteins,wrote eloquently and forcibly about the genetic code andtranslation prior to the time I met him, he was not (at thattime) a member of the National Academy of Sciences. And Isensed that Carl was disappointed, for good reason, that hismany contributions to science were not properly recognized.I fondly remember visiting Harry in Santa Cruz a few monthsafter I started my postdoc with Carl. I told Harry that Carl saidthat if he does not get elected into the National Academywithin the next two years, he will reject it in the event he iselected into this prestigious academy. Harry started laughingand laughing (and laughing). I asked, “What is so funny?”“Carl made the same statement to me three years ago.” Carlwas elected into the National Academy two years later. Carlhas received many awards, most of which were received afterbecoming a member of the National Academy. Carl was aMacArthur Fellow in 1984, was made a member of theNational Academy of Sciences in 1988, received the Leeu-wenhoek Medal (microbiology’s highest honor) in 1992 andthe Selman A. Waksman Award in Microbiology in 1995from the National Academy of Sciences, and was a NationalMedal of Science recipient in 2000. In 2003, he received theCrafoord Prize from the Royal Swedish Academy of Sciences“for his discovery of a third domain of life.” In 2006, he wasmade a foreign member of the Royal Society. I sensed thatCarl was indeed proud of his recognition, but more proud ofhis contributions to science.REFERENCESAndronescu M, Condon A, Hoos HH, Mathews DH, Murphy KP. 2010.Computational approaches for RNA energy parameter estimation.RNA 16: 2304–2018.Crick FH. 1968. The origin of the genetic code. J Mol Biol 38: 367–379.Do CB, Woods DA, Batzoglou S. 2006. CONTRAfold: RNA secondarystructure prediction without physics-based models. Bioinformatics22: e90–e98.Dyson F. 2007. Our biotech future. New York Rev Books 54: 4–8.Editorial. 2011. And the winner should be. Nat Rev Micro 9: 696.Fox GE, Woese CR. 1975. 5S RNA secondary structure. Nature 256:505–507.Gardner DP, Ren P, Ozer S, Gutell RR. 2011. Statistical potentials forhairpin and internal loops improve the accuracy of the predictedRNA structure. J Mol Biol 413: 473–483.Gutell RR, Woese CR. 1990. Higher order structural elements in ribo-somal RNAs: Pseudo-knots and the use of noncanonical pairs.Proc Natl Acad Sci 87: 663–667.Gutell RR, Weiser B, Woese CR, Noller HP. 1985. Comparative anatomyof 16-S-like ribosomal RNA. Prog Nucleic Acid Res Mol Biol 32:155–216.Gutell RR, Noller HF, Woese CR. 1986. Higher order structure in ribo-somal RNA. EMBO J 5: 1111–1113.Gutell RR, Larsen N, Woese CR. 1994. Lessons from an evolving rRNA:16S and 23S rRNA structures from a comparative perspective.Microbiol Rev 58: 10–26.Gutell RR, Lee JC, Cannone JJ. 2002. The accuracy of ribosomal RNAcomparative structure models. Curr Opin Struct Biol 12: 301–310.Levitt M. 1969. Detailed molecular model for transfer ribonucleic acid.Nature 224: 759–763.Noller HF, Kop J, Wheaton V, Brosius J, Gutell RR, Kopylov AM,Dohme F, Herr W, Stahl DA, Gupta R, et al. 1981. Secondarystructure model for 23S ribosomal RNA. 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  6. 6. Orgel LE. 1968. Evolution of the genetic apparatus. J Mol Biol 38:381–393.Orgel LE, Crick FH. 1993. Anticipating an RNA world. Some past spec-ulations on the origin of life: Where are they today? FASEB J 7:238–239.Woese CR. 1965a. On the evolution of the genetic code. Proc Natl AcadSci 54: 1546–1552.Woese CR. 1965b. Order in the genetic code. Proc Natl Acad Sci 54:71–75.Woese CR. 1967. The genetic code: The molecular basis for geneticexpression (modern perspectives in biology). Harper & Row, NewYork.Woese CR. 1969. The biological significance of the genetic code. InProgress in molecular and subcellular biology (ed. FE Hahn), pp.27–68. Springer-Verlag, New York.Woese C. 1970a. The problem of evolving a genetic code. BioSci 20:471–485.Woese C. 1970b. Molecular mechanics of translation: A reciprocatingratchet mechanism. Nature 226: 817–820.Woese CR. 1970c. The genetic code in prokaryotes and eukaryotes. InOrganization and control in prokaryotic and eukaryotic cells (ed.HP Charles, BCJG Knight), pp. 39–54. Cambridge UniversityPress, Cambridge, UK.Woese CR. 1973. Evolution of the genetic code. Naturwissenschaften 60:447–459.Woese CR. 1977. Endosymbionts and mitochondrial origins. J Mol Evol10: 93–96.Woese CR. 1980. Just so stories and Rube Goldberg machines:Speculations on the origin of the protein synthetic machinery. InRibosomes: structure, function, and genetics (ed. G Chambliss, etal.), pp. 357–373. University Park Press, Baltimore, MD.Woese CR. 1987. Bacterial evolution. Microbiol Rev 51: 221–271.Woese CR. 2000. Interpreting the universal phylogenetic tree. Proc NatlAcad Sci 97: 8392–8396.Woese CR. 2001. Translation: In retrospect and prospect. RNA 7:1055–1067.Woese CR. 2004. A new biology for a new century. Microbiol Mol BiolRev 68: 173–186.Woese CR, Fox GE. 1977a. Phylogenetic structure of the prokaryoticdomain: The primary kingdoms. Proc Natl Acad Sci 74: 5088–5090.Woese CR, Fox GE. 1977b. The concept of cellular evolution. J Mol Evol10: 1–6.Woese CR, Gutell RR. 1989. Evidence for several higher order structuralelements in ribosomal RNA. Proc Natl Acad Sci 86: 3119–3122.Woese CR, Dugre DH, Saxinger WC, Dugre SA. 1966. The molecularbasis for the genetic code. Proc Natl Acad Sci 55: 966–974.Woese CR, Magrum LJ, Gupta R, Siegel RB, Stahl DA, Kop J,Crawford N, Brosius J, Gutell R, Hogan JJ, et al. 1980. Secondarystructure model for bacterial 16S ribosomal RNA: Phylogenetic, en-zymatic and chemical evidence. Nucleic Acids Res 8: 2275–2293.Woese CR, Gutell R, Gupta R, Noller HF. 1983. Detailed analysis of thehigher-order structure of 16S-like ribosomal ribonucleic acids.Microbiol Rev 47: 621–669.Woese CR, Winker S, Gutell RR. 1990. Architecture of ribosomal RNA:Constraints on the sequence of “tetra-loops”. Proc Natl Acad Sci 87:8467–8471.Yang D, Oyaizu Y, Oyaizu H, Olsen GJ, Woese CR. 1985. Mitochondrialorigins. Proc Natl Acad Sci 82: 4443–4447.R.R. GutellSection of Integrative BiologyUniversity of Texas at Austinwww.rnajournal.org xiIn memoriamCold Spring Harbor Laboratory Presson March 19, 2013 - Published byrnajournal.cshlp.orgDownloaded from